3-Hydroxy-3-morpholino-loweralkyl-3,4-dihydro-2H-1,5-benzodioxepin products

ABSTRACT

3-Hydroxy-3-(substituted-aminoalkyl,-3,4-dihydro-2H-1,5benzodioxepin products are described that exhibit Beta adrenergic stimulating properties and are therefore suitable for use as bronchodilating agents. The products are prepared essentially by four principal routes from 3-oxo-3,4-dihydro-2H1,5-benzodioxepins. By one route the 3-oxobenzodioxepin is treated with a nitroalkano to give a 3-hydroxy-3-nitroalkylbenzodioxepin the nitro group of which is reduced to an amine and the resulting compound reacted with an aldehyde or ketone under hydrogenating conditions to introduce the desired substituent into the amino function. By a second route the 3-oxobenzodioxepin is reacted with an alkali metal nitrile to form the cyanhydrin which upon reduction forms the 3-hydroxy-3-aminoalkylbenzodioxepin that can be treated with a ketone or aldehyde to give the desired products or can be reacted with sodium nitrite or other agent to form a 3-spiro-benzodioxepin-2&#39;&#39;-oxirane which upon reaction with an amine provides the desired product. The 3spiro-benzodioxepin-2&#39;&#39;-oxirane also can be obtained by treatment of the 3-oxo-benzodioxepin with a sulfurylide. A fourth method involves forming a benzodioxepin-3-spiro-3&#39;&#39;-oxazolidin-2&#39;&#39;-one which upon treatment with dilute alkali gives the desired 3hydroxy-3-(substituted aminoalkyl)-3,4-dihydro-2H-1,5benzodioxepin. The intermediate oxazolidinone compounds can be treated if desired with various agents to attach substituents on the benzenoid moiety of the starting substance. These oxazolidinones exhibit Beta -stimulating and skeletal muscle relaxant properties.

United States Patent [1 1 Wasson et al.

[451 Sept. 23, 1975 3-HYDROXY-3-MORPHOLINO- LOWERALKYL-3,4-Dll YDRO-2ll-1,5- BENZODIOXEPIN PRODUCTS [75] Inventors: Burton K. Wasson, Valois; Haydn W. R. Williams, Dollard des Ormeaux, both of Canada [73] Assignee: Merck & Co., Inc., Rahway, NJ. [22] Filed: Nov. 21, 1973 [2]] Appl. No.: 417,869

Related US. Application Data [62] Division of Ser. No. 249,422, May 1, I972, Pat. No. 3,812,150, which is a division of Ser. No. 832,879, June 9, 1969, Put. NO. 3,700,691.

[52] Int. Cl....260/247.7 A; 260/247.1 R; 260/2472 [51] Int. Cl C07d 87/32 [58] Field of Search260/247.l R, 247.2 B, 247.5 R,

Primary Examiner-John D. Randolph Attorney, Agent, or Firm-David L. Rose; 1. Jerome Behan [57] ABSTRACT 3-Hydroxy-3-(substituted-ami.n0alkyl,-3,4-dihydro-2H- 1,5-benzodioxepin products are described that exhibit B-adrenergic stimulating properties and are therefore suitable for use as bronchodilating agents. The products are prepared essentially by four principal routes from 3-oxo-3,4-dihydr0-2H-l,5 benzodioxepins. By one route the 3oxobenzodioxepinis treated with a nitroalkano to give a 3-hydroxy-3-nitroalkylbenzodioxepin the nitro group of which is reduced to an amine and the resulting compound reacted with an aldehyde or ketone under hydrogenating conditions to introduce the desired substituent into the amino function. By a second route the 3-oxobenzodioxepin is reacted with an alkali metal nitrile to form the cyanhydrin which upon reduction forms the 3-hydroxy-3- aminoalkyl-benzodioxepin that can be treated with a ketone or aldehyde to give the desired products or can be reacted with sodium nitrite or other agent to form a 3-spiro-benzodioxepin-2-oxirane which upon reaction with an amine provides the desired product. The 3-spiro-benzodioxepin-2'-oxirane also can be obtained by treatment of the 3-oxo-benzodioxepin with a sulfurylide. A fourth method involves forming a benzodioxepin-3-spiro-3-oxazolidin-2-one which upon treatment with dilute alkali gives the desired 3-hydroxy-3- (substituted aminoalkyl)-3,4-dihydro-2l-l-l ,5- benzodioxepin. The intermediate oxazolidinone compounds can be treated if desired with various agents to attach substituents on the benzenoid moiety of the starting substance. These oxazolidinones exhibit B-stimulating and skeletal muscle relaxant properties.

5 Claims, N0 Drawings 3-HYDROXY-3-MORPHOLINO-LOWERALKYL- 3,4-DlHYDlRO-2H-l ,S-BENZODIOXEPIN PRODUCTS This is a division of application Ser. No. 249,422 filed May 1,1972, now US. Pat. No. 3,812,150 granted May 21, 1974 which in turn was a division of the then copending application, Ser. No. 832,879, tiled June 9, 1969, now US. Pat. No. 3,700,691 granted Oct. 24, 1972.

This invention is concerned with 3,3-disubstituted benzodioxepins which exhibit ,B-adrenergic stimulating properties which make them uniquely suitable for use as broncho-dilating agents.

The novel 3,3-disubstituted benzodioxepins of this invention can be illustrated by the structural formula and pharmacologically acceptable salts thereof wherein R is selected from hydrogen, hydroxy, lower alkyl (C,-,-,) and lower alkoxy (C R is selected from hydrogen, halogen particularly chloro and bromo, lower alkyl (C nitro, amino, monoor di-lower alkylamino, acrylamino wherein the acyl radical is the residue of an alkyl (C sulfonic acid or an alkyl (C carboxylic acid, lower carboalkoxyamino, hydroxy or lower alkoxy (C X and X are selected from hydrogen, lower alkyl (C and halogen; R and R can be the same or dissimilar and are each separately selected from hydrogen, lower alkyl (C phenyl or phenyl-lower alkyl (C lower cycloalkyl, pyridyl and pyridyl-lower alkyl (C R is selected from hydrogen and lower alkyl (C and the grouping NR 'R represents the amino group or a monoor di-substituted amino group or a nitrogen containing heterocyclic group and in particular an -NR R group where R represents hydrogen, lower alkyl (C and substituted lower alkyl such as 2-phenyl-2- hydroxyethyl, and R represents (1) lower alkyl having advantageously from 1 to 10 carbon atoms and being either straight or branched chain, and being either unsubstituted or substituted with one or more groups selected from (at) amino or monoor di-loweralkyl (C,- amino, or the amino substituent can be wherein R, R and X have the above assigned meanings, (b) cycloalkyl having from 3 to 6 carbon atoms, (c) lower alkoxy having from 1 to 3 carbon atoms, (d) hydroxy substituted lower alkoxy having from 1 to 3 carbon atoms, (e) hydroxy, (f) phenyl or monoor poly-substituted phenyl wherein the substituents are selected from halo especially chloro or bromo, hydroxy and lower alkoxy (C or wherein the substituted phenyl is the 3,4-methylenedioxyphenyl, (g) a heterocyclic substituent such as an indolyl, morpholino or 1,2,5-thiadiazolyloxy, (2) a cycloaliphatic such as a cycloalkyl having from 3 to 10 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tricyclodecane such as adamantyl and the like, or a phenyllowercycloalkyl as phenyl-cyclohexyl, (3) lower alkenyl having from 3 to 5 carbon atoms, (4) lower alkynyl having from 3 to 5 carbon atoms, (5) phenyl or substituted phenyl wherein the monoor poly-substituents are selected from a halogen such as chloro and bromo, lower alkyl (C, and lower alkoxy (C (6) a heterocyclic substituent such as 2-pyridyl, (7) the residue of a guanidine moiety of the structure wherein R is hydrogen, lower alkyl, benzyl or phenyl or substituted phenyl wherein the substituent is one or more groups selected from halo, especially chloro or bromo, lower alkyl (C or lower alkoxy (C (8) the benzodioxepin radical wherein R, R and X have the above assigned meanings, but preferably they represent hydrogen; and in addition the grouping NR-R can represent a morpholino, piperazinyl, N-phenyl-pip erazinyl, l-aziridinyl or 3-(2-iminothiazolidinyl) group.

The novel 3,3-disubstituted benzodioxepins of this invention advantageously are prepared by the reactions illustrated in Flow Diagram 1.

- FLOW DIAGRAM I NO 2 Alkane H-NOZ Alkyl H as "Al;

Reduction "C II Reduction 0 Sulfur ylide R1 \0 Ru R H H NHNQ CH-NH fin l) aldehyde or ketone H catalyst x 2 R3 1 0 on 0 ('IHNR5R6 R14 R a n According to the above reaction scheme it is seen that the desired 3,4 dihydro-ZH-l ,5benzod ioxepin, product I, is obtained from the 3-keto compound A by one of two methods depending upon whether R" is hydrogen or whether it represents a lower alkyl group of from 1 to 4 carbons. Additionally, the 3-keto compound A can be directly converted to the 3-spiro-2- oxirane B by use of a sulfur ylide.

When R is hydrogen, the 3-keto intermediate A in an acidic solvent is caused to react with aqueous hydro- HNRSRS gen cyanide, conveniently generated in situ from sodium or potassium cyanide to provide the 3-hydroxy-3- cyano intermediate C which is separated and reduced to provide the 3-hydroxy-3-aminoalkyl intermediate D. Treatment of intermediate D with acetone or other ketone or aldehyde that will yield the group R upon reduction provides the desired product 1. Intermediate D also can be treated with an alkali nitrite to form the 3- spiro-2'-oxirane E which when reacted with the desired amine forms product I.

The first step of the above procedure, that is treat- 'anide. advantageously is carried out in the presence of acetic 'anhydride or other acidic solvent, e,g., acetic acid or alternatively with anhydrous hydrogen cyanide. The reduction of intermediate C canbe either a cat'alytic or chemical reduction; catalytic reduction preferably being carried out with a transition metal catalyst such as platinum, palladium, nickel, ruthenium, rhodium and the like in a mixture ofa lower alkanol(C and acetic acid supplemented if necessary with a trace of mineral acid, i.e. hydrochloric acid, or if desired chemical reduction can be effected with a metal hydride advantageously lithium aluminum hydride or other metal hydrides, preferably in diethyl ether or tetrahydrofuran. Each method affords good yields of product D.

Intermediate D then can be converted to the desired 3,3-disubstituted benzodioxepin I of this invention by either of two routes. One of the routes employed for preparing product I wherein R is hydrogen, involves the reaction of intermediate D with a ketone or aldehyde that will'yield the group R and subsequent reduction advantageously carried out by hydrogenation in the presence of a transition metal catalyst in an organic solvent such as a lower alkanol as ethanol, propanol, butanol or isomers thereof and the like, employing acidic conditions when required or chemical reduction with sodium borohydride can be employed.

The second more general method for preparing product I where R and R have the meaning given above involves the reaction of intermediate D with an alkyl nitrite or with nitrous acid generated in situ from an alkali metal nitrite (sodium or potassium nitrite being quite suitable) advantageously carried out in an aqueous medium in the presence of an organic acid, acetic acid being preferred, and advantageously with cooling to provide a 3-spiro-2-oxirane E as well as the 3-hydroxy-3-hydroxymethyl analog The novel 3-hydroxy-3-hydroxymethyl products also exhibit ,B-adrenergic stimulating properties, and constitute another feature of this invention. The 3-spiro-2-oxirane E obtained then is reacted with the amine, HNR R, advantageously in the presence of an organic solvent such as a lower alkanol at ambient temperature to give the benzodioxepin I. product I wherein R and R represent hydrogen with an S-loweralkylisothiuronium salt of the structure advantageously with heating up to about the reflux temperature of the reaction mixture. Whenl lR"R in product I is the I-aziridinyl group, treatment of said compound with sodium thiocyanate under acid conditions (pH no greater than 4) provides product I wherein NR R' is the 3-(2-iminothiazolidinyl) group.

Product I wherein R, R, X and R represent hydrogen can be employed starting materials to prepare end products wherein R, R and X are other than hydrogen and particularly where R is nitro, amino, lower acylamino and hydroxy. These latter compounds can be prepared by the methods described above or by initially treating a 3-hydroxy-3-(RNH-CH benzodioxepin with phosgene in the presence of a base.

Phosgene advantageously in admixture with chloroform is added dropwise with stirring to a cooled solution of the benzodioxepin in the same SOlVt.:Il. The 3-spiro-5-oxazolidin-2-one obtained is admixed with acetic acid, cooled to the freezing point and treated dropwise with a mixture of nitric acid and sulfuric acid to provide the corresponding 7-nitro-3-spiro-5- oxazolidin-2-one compound which in the presence of dilute alkali, as aqueous sodium or potassium hydroxide, gives the desired 7-nitro-3-hydroxy-3-(RNHCH )benzodioxepin, I-a.

Catalytic reduction of I-a or its intermediate 7-nitro- 3-spiro-5-oxazolidin-2-one, advantageously with palladium or Raney Nickel, provides the corresponding 7-amino derivative. The 7-amino-3-spiro-5-oxazolidin- 2-one when treated with aqueous alkali gives the 7- amino-3-hydroxy-3-(RNHCH -)benzodioxepin, I-b.

Product I-a also can be converted to the 7-amino analog, 1-1), or to the 7-lower acylamino by first reacting I-a with an aldehyde YCHO, wherein Y can be lower alkyl, phenyl or the residue of any commercially available aliphatic or aromatic aldehyde, to form the 7- nitro-2-Y-3-spiro-5-oxazolidine which, upon reduction as described above, gives the corresponding 7- amino compound which can either be treated with aqueous alkali to provide product H2 or treated with a lower alkyl sulfonyl halide or a lower alkanoyl halide to give the corresponding 7-aeylamino-2'-Y-3-spiro-5'- oxazolidine which when treated with acid, especially with a mineral acid or strong organic acid, gives the 7- acylamino-3-hydroxy-3-(RNHCH -)benzodioxepin, I-c.

Diazotization of the 7-amino-3-spiro-5-oxazolidin- 2-one, prepared as described above, gives the corresponding 7-hydroxy compound which, in the presence of base, such as barium hydroxide gives 3,7-dihydroxy- 3-(R NHCI-I )benzodioxepin, 1-41.

The 6- and/or 7-hydroxy-benzodioxepins, I, also can be prepared from the corresponding 6- and/or 7-alkoxy-benzodioxepins by treatment with strong mineral acid.

The 3-spiro-2'-oxirane E can also be prepared by treatment of the 3-keto compound A with either dimethylenesulfonium methylide or dimethylsulfonium methylide either with cooling or at a temperature up to ambient temperature. In practice, the dimethyloxosulfonium methylide is prepared under nitrogen from sodium hydride, trimethyloxosulfonium iodide and dimethyl sulfoxide. The ketone, A, is added slowly to the mixture at ambient temperature and the mixture stirred for about 24 hours. The dimethylsulfonium methylide advantageously is prepared from butyl lithium and trimethylsulfonium iodide in tetrahydrofuran. The ketone A then is added and the reaction mixture held at 0 C. for 1 hour and then for a short period at ambient temperature. Isolation in each instance provides the desired 3-spiro-2'-oxirane, E.

To prepare the products wherein R is a lower alkyl group, the ketone A initially is reacted with a nitroalkane to give intermediate B which upon reduction provides intermediate D. The reaction of the ketone A with the nitro-alkane advantageously is carried out in ethanol or other lower alkanol or ether in the presence of sodium ethoxide or other alkali metal alkoxide to give a salt of B from which the compound is liberated by treatment with a weak acid such as acetic acid. The reduction of intermediate B to form D is effected advantageously in ethanol (or other lower alkanol )-acetic acid with hydrogen and Raney Nickel or palladium.

While the unsubstituted 3-keto compound A is known, it was obtained in low yields as a by-product in the preparation of l.4-benzodioxane-3-carboxylic acid. All attempts by these investigators to prepare the 3-keto-benzodioxepin either failed or provided very small yields of the desired product. Avprocess thus had to be devised for the preparation of this ketonewhich has been found to give very high yields ofhcompound A. This novel synthetic route for the preparation of the 3- keto compound A can be illustrated as showntin Flow Diagram ll.

FLOW DIAGRAM II R2 R3 x i x X]. x l 1 x o-c-cu 0H k Y-CR2R3-CN 1 z 3 Mk 0 c CO Al R1 O CH2-C R1 R CH2CO2Alk R R R "F1.- "E" "F2" Cyclization Cyclization Agent Agent 3 x R R3 1 0 X H2 0 ll R 0 R1 0 R CN R CO Alk' "G1" "G2" hydrolysis and decarboxylation hydrolysis and decarboxylation x 2 R x 'R H H "All Azacycle (when/R land R H) X, X I

X H X 0 R H H Alkylation and hydrolysis According to the reaction scheme illustrated in Flow Diagram ll, the catechol starting material E is converted to the 3-keto product A by initial reaction with a haloalkanonitrile or a haloalkanoic acid ester.

Treatment of the catechol E with a halo-acetonitrile of the structure YCR-RCN, to afford the 1,2 bis-(cyanoalkoxy)-benzene, F, is carried out in one step when R and R each represent hydrogen, however, when it is desired to form product F wherein R and R are other than hydrogen, then the catechol (X=X=R=R=H) initially is treated with one equivalent of halo-acetonitrile, the orthocyanomethoxyphenol isolated and then reacted with the haloalkanonitrile to give F wherein R and/or R are other than hydrogen.

When X, X, R or R is other than hydrogen then it is preferred to use the appropriately substituted salicylaldehyde which is treated with the appropriate haloalkanonitrile, and the resulting compound oxidized by peracetic acid followed by mild hydrolysis to give the orthocyano-alkoxyphenol which then is treated with haloacetonitrile to provide F. Product F then is cyclized by treatment with amixture of sodamide and a solvent selected preferably from dimethyl sulfoxide (DMSO), dimethylformamide (DMF), sulfolane, benezene, toluene or xylene or by treatment with an alkali metal t.-butoxide or other alkali metal, t.-alkanolate in DMSO, DMF, benzene, toluene, xylene, sulfolane or a t.-alkanol corresponding to the alkanolate employed, or by treatment with sodium or potassium, lower alkanolate, sodium hydride, potassium-sodium amalgam (l:l) lithio or sodio-N-methylaniline, to form the 3- amino-4-cyano-2H-l ,S-benzodioxepin, G. Best results are obtained when this step is carried out in an inert atmosphere such as under nitrogen or other inert gas such as argon or other usual inert gas. Intermediate G is hydrolyzed and decarboxylated to the ketone A either by first refluxing in aqueous acetic acid followed by refluxing with phosphoric acid, or by acid alcoholysis followed by heating in aqueous alkanol to effect hydrolysis and decarboxylation. While intermediate G is illustrated as having the structure 3-amino-4-cyano, its tautomer, 3-imino-4-cyano-3,4-dihydro-2H-l ,5- benzodioxepin may also be present. It is understood that when X,X, R and/or R is/are other than hydrogen, additional isomers are possible. However, upon hydrolysis with concomitant decarboxylation by either of the above procedures all tautomers or isomers are converted to the 3-keto compound A.

When X,X, and all Rs in compound A are hydrogen, this product, if desired, can be reacted with an azacycle such as morpholine, piperidine. pyrrolidine, and the like to give the 3-azacyclic substituted compound H which when treated with an alkylating agent as a lower alkyl iodide or bromide, dialkylsulfate or trialkyloxoniumtetrafluoroborate, provides the desired 2-mono-substituted-3-keto compound A.

The second of the principal methods for making compound A from the catechol E involves initial reaction of E with a halo-alkanoic acid ester, halo-CR R"-CO alkyl, to give the l,2-bis-alkoxycarbonylalkoxybenzene, F When R- and R in compound F are each hydrogen. compound F is produced in one step.

When R and/or R are other than hydrogen, then the catechol (X=X=R=R=H) initially is treated with haloacetic acid ester. the ortho-alkoxycarbonylmethoxyphenol isolated and then reacted with a haloalkanoic acid ester to give F wherein R and/or R are other than hydrogen. When X,X, R and/or R is/are other than hydrogen, preferably the appropriate salicylaldehyde is reacted with YCR RCO alkyl wherein R and/or R is other than hydrogen and the resulting compound oxidized by peracetic acid followed by mild hydrolysis to give the ortho-alkoxycarbonylalkoxyphenol or the corresponding acid which can be reesterified. The ester then is treated with an alkyl haloacetate to provide intermediate F Cyclization of compound F to form G is effected by substantially the same method described above for the cyclization of F to provide G. Hydrolysis and decarboxylation of G by acid hydrolysis in a lower alkanol advantageously by employing aqueous hydrochloric acid in methanol or ethanol followed by heating gives the desired 3-keto compound A.

The pharmacologically acceptable salts of the benzodioxepins of this invention are prepared by the reaction of product I with an inorganic or organic acid such as hydrochloric, hydrobromic, sulfuric, phosphoric, formic, acetic, succinic, lactic, malic, tartaric, citric, maleic, phenylacetic, benzoic, salicyclic, or p-toluenesulfonic acid or similar acidsthat are known to provide pharmacologically acceptable salts.

The benzodioxepins however can be employed in pharmaceutical formulations either in the form of free bases or in the form of their acid addition salts in conjunction or admixture with organic or inorganic solid or liquid pharmaceutical excipients. These pharmaceutical formulations can be in the form of tablets, solutions, suspensions, emulsions, or aerosols suitable for oral or topical administration.

Unlike hitherto known bronchodilators which generally are short acting, the benzodioxepin products of this invention exhibit a long duration of activity. The compounds were found when tested according to accepted and standard laboratory procedures in guinea pigs to be orally effective within a dosage range of from about 1 mg. to about 20 mg./kg. and when administered intravenously the effective dosage range was between 10 microg/kg. to 2 mg./kg. At these dosages the products were acceptably tolerated by the animals.

The 3 -R-6-R-7-R-3,4-dihydro-2H-l ,5- benzodioxepin-3-spiro-5 '-oxazolidin-2 '-one compounds prepared in the synthesis of the principal products of this invention, are also novel and form another feature of this invention. In addition to exhibiting bronchodilating properties, these compounds also exhibit muscle relaxing properties and are therefore useful in the relief of spastic states.

The following examples will illustrate the preparation of representative products of this invention prepared by the above-described procedures. It will be understood that while all of the compounds can be prepared by the procedure described in the following examples, modifications of the procedural steps which would be obvious to the skilled chemist can be employed. The following examples therefore are not to be considered as limiting the preparation ofany particular compound to the precise procedural steps described in the examples which are provided solely to illustrate the best mode currently known to applicant.

Where the term benzodioxepin is employed in the disclosure and claims it is to be understood to mean 3,- 4-dihydro-2H-1,S-benzodioxepin.

The following examples describe the preparation of the novel products of this invention by the route A 'C D l illustrated in Flow Diagram I.

EXAMPLE 1 3-Hydroxy-3-isopropylaminomethyl-3 ,4-dihydro-2H- l,5benzodioxepin Hydrochloride of acetone is refluxed with stirring for l and V2 hours.

The mixture then is treated with 45.3 g. (0.6 mole) of chloroacetonitrile and 84 g. (0.608 mole) of potassium carbonate, and refluxed for a further 3.5 hours. The mixture is filtered, the solids washed with 150 ml. of acetone and the combined filtrate evaporated in vacuo to give an oil. The oil which crystallizes is recrystallized from ethanol-water (8:1) to give 138 g. (81.5%) of 1,2-di-(cyanomethoxy)benzene, m.p. 85.0-86.5 C. Further recrystallization from the same solvent system affords the product melting at 85.085.5 C.

Analysis calculated for c,,,H,,N o,. C, 63.82; H, 4.29; N, 14.89. Found: C, 64.17; H, 4.48; N, 14.94. Step B: Preparation of 3-amino-4-cyano-2H-l,5- benzodioxepin Sodamide (49.2 g., 1.26 mole) is added with stirring under nitrogen to 370 ml. of dry dimethyl sulfoxide. After the initial vigorous evolution of ammonia has subsided the solution is heated /2 hour at 60 C. A solution of 115.8 g. (0.616 mole) of 1,2-di-(cyanomethoxy)benzene in 246 ml. of dimethyl sulfoxide is added with stirring and cooling (water bath at ambient temperature) during 1 hour and the reaction mixture stirred for a further 2 hours at ambient temperature. A mixture of 81.5 ml. of acetic acid and 246 ml. of water isadded slowly accompanied by stirring and cooling.

.The mixture is poured into 1.2 liters of water and the tan-colored solids collected. The solids are recrystallized from chloroform to give 75.5 g. (65%) of 3- amino-4-cyano-2H-l ,5-benzodioxepin, m.p. 167-169 C. Further recrystallization from chloroform affords the product melting at 168169 C.

Analysis calculated for C,,,H,,N O C, 63.82; H, 4.29; N, 14.89. Found: C, 63.80; H, 4.35; N, 14.70.

Alternatively the above 3-amino-4-cyano-2H-l ,5- benzodioxepin can be prepared as follows.

A solution of 9.4 g. (50 millimoles) of l,2-di-(cyanomethoxy)benzene in 20 ml. of dimethyl sulfoxideis added under nitrogen to a stirred mixture of 12.3 g. (l 10 millimoles) of potassium tert.-butoxide in 30 ml. of dimethyl sulfoxide cooled in a water bath at ambient temperature. The mildly exothermic reaction raises the internal temperature of the mixture to 42 C. The mixture is stirred a further 2 hours and a solution of 6.6 ml. of acetic acid in 20 ml. of water added slowly with cooling. [Alternatively, the reaction mixture can be poured into the aqueous acetic acid solution.] The product is precipitated by pouring the mixture into 100 ml. ofwater. The beige-colored solid is collected, washed with water, and air dried to give 9.5 g. of crude product, m.p. 148-154 C. The crude product is recrystallized from 200 ml. of chloroform to afford 5.8 g. (6l.7%) of 3-amino-4-cyano-2H-1,5- benzodioxepin. A mixed melting point with the product obtained above gave no depression.

Step C: Preparation of 3-oxo-3,4-dihydro-2H-l ,5- benzodioxepin A mixture of 16.0 g. (85.1 millimoles) of 3 amino-4- cyano-ZH-l ,S-benzodioxepin, 18 m1. of water, and 300 ml. of acetic acid is refluxed V2 hour. The mixture is treated dropwise with 120 ml. phosphoric acid and then refluxed overnight. The solution is cooled to ambient temperature, and poured onto 500 g. of crushed ice. Ammonium sulfate (180 g.) is added and the solution continuously extracted with ether for several hours. The ethereal solution is evaporated to dryness to remove ether and acetic acid, and the residual oil dissolved in diethyl ether, washed with 10% sodium carbonate solution, dried, and evaporated. The resulting oil is fractionated to give 8.96 g. (64%) of 3-oxo- 3,4-dihydro-2H-l,5-benzodioxepin, b.p. 52-61 C. at 0.07 mm pressure, which at first is a colorless oil which solidifies. The product is used directly in the next step. Step D: Preparation of 3-hydroxy-3-cyano-3,4-dihydro- 2H-1,5-benzodioxepin A solution of 13.5 g. (208 millimoles) of potassium cyanide in 27 ml. of water is added dropwise to a mixture of 18.7 g. (1 14 millimoles) of 3-oxo-3,4-dihydro- 2H-1,5-benzodioxepin and 21.2 g. (208 millimoles) of acetic anhydride with stirring and cooling. The mixture is stirred at ambient temperature overnight and then is made alkaline with 10% sodium carbonate solution. The product in the form of an oil is extracted with diethyl ether, treated with charcoal and dried over calcium sulfate. Evaporation of the solvent gives a solid that is recrystallized from carbon tetrachloride to give 3-hydroxy-3-cyano-3,4-dihydro-2H-1,5-benzodioxepin as plates, m.p. 108.5l 10 C.

Analysis calculated for C H NO C, 62.82; H, 4.74; N, 7.33. Found: C, 62.70; H, 4.54; N, 7.09.

An alternative method for preparing 3-hydroxy-3- cyano-3,4-dihydro-2H-l,S-benzodioxepin can be carried out in the following manner.

To a stirred solution of 4.92 g. (30 millimoles) of 3- oxo-3,4-dihydro-2H-1,5-benzodioxepin in ml. of benzene is added dropwise a solution of 30 millimoles of anhydrous hydrogen cyanide in 50 ml. of benzene. The reaction mixture is stirred overnight at ambient temperature, basified with 10% sodium carbonate solution and the organic layer separated. The benzene solution is washed once with water and dried successively over anhydrous magnesium sulfate and calcium sulfate. Evaporation of the solvent under reduced pressure at 40 C. yields the crude cyanohydrin which upon purification and mixed melting point determination gives no depression with an authentic sample-of 3-hydroxy-3- cyano-3,4-dihydro-2H-l ,S-benzddioxepln.

Step E: Preparation of 3-hydroxy-3-aminomethyl-3,4- dihydro-ZH-l ,S-benzodioxepin hydrochloride A mixture of 9.5 g. (49.7 millimoles) of 3-hydroxy-3- cyano-3,4-dihydro-2H-1,5-benzodioxepin, 75 ml. of anhydrous ethanol, and 3 m1. of acetic acid is shaken under hydrogen at ambient temperature and pressure in the presence of 100 mg. of platinum oxide and a little ethanolic-hydrogen chloride. The catalyst is removed and the filtrate evaporated to dryness to give 5.2 g. of crude product, m.p. 2072l4 C. Recrystallization of this crude product from isopropanol afford 3-hydroxy- 3-aminomethyl-2,4-dihydro-2H-1,S-benzodioxepin hydrochloride, m.p. 228230 C. (clearing at 238 C.)

Analysis calculated for C H, NO .HCl. C, 51.84; H, 6.09; N, 6.06. Found: D, 52.11; H, 6.13; N, 5.86.

An alternative method for preparing 3-hydroxy-3- amino-methyl-3,4-dihydro-2H-1,S-benzodioxepin can be carried out in the following manner.

3-Hydroxy-3-cyano-3,4-dihydro-2H-l .5- benzodioxepin (30 millimoles) is dissolved in 100 ml. of dry diethyl ether and the solution added dropwise during a period of 0.75 hours under dry nitrogen to a stirred slurry of 3.8 g. (100 millimoles) of lithium aluminum hydride in 100 ml. of dry ether. The mixture is stirred under reflux for 2.25 hours and treated carefully with 3.8 ml. of water. An easily-fllterable precipitate of metallic compounds is obtained by the dropwise addition of 5.7 ml. of sodium hydroxide solutionn followed by 1 1.4 ml. of water. The ethereal solution is fil' tered and the filter-cake then is washed with 50 ml. of diethyl ether. The combined filtrate is dried over anhydrous magnesium sulfate and again over calcium sulfate before evaporation in a rotary film-evaporator to yield 5.13 g. (87%) ofthe free base as a colorless solid, mp. 60-63 C. (to a turbid melt). This product, upon recrystallization from benzene from which it separates as colorless plates melts at 6668 C. A solution of 3.0 g. of the base dissolved in dry diethyl ether is treated with a slight excess of approximately 5N ethanolichydrogen chloride solution affording 2.82 g. of 3- hydroxy-3-amino-methyl-3,4-dihydro-2H-l ,5- benzodioxepin hydrochloride. This product gives no depression in melting point when admixed with authentic material prepared by the catalytic reduction of the cyanohydrin, as described above.

Step F: Preparation of 3-hydroxy-3- isopropylaminomethyl-3,4-dihydro-2H-1,5- benzodioxepin hydrochloride A mixture of 3.92 g. 16.95 millimoles) of 3-hydroxy- 3-aminomethyl-3,4-dihydro-2H-l ,S-benzodioxepin hydrochloride, 1.39 g. (16.95 millimoles) of anhydrous sodium, acetate, and 80 ml. of anhydrous ethanol is stirred under nitrogen for minutes. Acetone (1.08 g., 18.6 millimoles) is added and the mixture stirred for minutes. The mixture is hydrogenated at ambient temperature and pressure for 1 and /2 hours over 100 mg. of platinum oxide. The catalyst is removed, the solution evaporated to a syrup, 60 ml. of dry diethyl ether added, and a slight excess of 9.7N ethanolic-hydrogen chloride solution added. The solids are collected to give 4.65 g. of crude product, m.p. 172-l75 C. The product is recrystallized from isopropanol to give 3.05 g. (65%) of 3-hydroxy-3-isopropyl-aminomethyl-3,4- dihydro-2H-l,S-benzodioxepin hydrochloride, m.p. l78.51 800 C.

Analysis calculated for C, H ,,NO .HCl. C, 57.04; H, 7.36; N, 5.11. Found: C, 56.95; H, 7.29; N, 4.89.

An alternative method for preparing the benzodioxepin of Step F can be carried out in the following manner.

3-Hydroxy-3-aminomethyl-3,4-dihydro-2H-1,5- benzodioxepin (195 mg., 1 millimole) is dissolved in isopropanol (3 ml.) and treated with acetone (64 mg., 1.1 millimoles). On standing overnight, the solution deposits a crystalline solid (glistening plates), and this is reduced in situ by the addition of sodium borohydride (75.6 mg., 2 millimoles). After stirring the mixture at ambient temperature for 3 hours water (20 ml.) is added and then 2.75N hydrochloric acid (1.5 ml.). The solution is extracted with ether 10 ml.) and the extract rejected. Glycerol (1 ml.) is added and the solution then is basified with 2N sodium hydroxide (5 ml.) to liberate the free base. The latter is extracted with ether (25 ml.), the ethereal solution washed with water (2 X 10 m.) and then dried thoroughly over magnesium sulphate followed by calcium sulphate. Addition of 5N ethanolic hydrogen chloride solution to the solution of base precipitated the 3-hydroxy3- isopropylaminomethyl-3.4-dihydro-2H-1,5- benzodioxepin hydrochloride (136 mg., 49.6% No depression of melting point is observed when the product is admixed with an authentic specimen of the compound.

EXAMPLE 2 3-Hydroxy-3-guanidinomethlyl-3,4dihydro-2H- l ,5- benzodioxepin sulfate 3-Hydroxy-3-aminomethyl-3,4-dihydro-2H-l ,5- benzodioxepin from Example 1, Step E, (1.95 g., 10 millimoles) and 2.78 g. (10 millimoles) of S- methylisothiourea sulfate in 15 mls. of dimethylformamide and 2 mls. of water is heated at -100 C. for 5 hours. The solvent is evaporated in vacuo and the residue recrystallized from ethanol to give 3-hydroxy-3- guanidinomethyl-3,4-dihydro-2H-1,S-benzodioxepin sulfate.

EXAMPLE 3 3-Hydroxy-3-( B-phenylguanidinyl )methyl3 ,4-dihydro- 2H-1 ,S-benzodioxepin hydriodide A mixture of S-methyl-N-phenylisothiourea hydriodide (2.94 g., 10 millimoles), 3-hydroxy'3- aminomethyl-3,4-dihydro-2ll-il ,5-benzodioxepin 1.95 g. (10 millimoles) from Example 1, Step E, and 20 mls. of ethanol is warmed until evolution of methyl mercaptan ceases and then is refluxed for 2 hours. The solution then is evaporated to a small volume and diluted with ether to give 3-hydroxy'3-(3-phenylguanidinyl)methyl- 3 ,4-dihydro-2H- 1 ,S-benzodioxepin hydriodide.

EXAMPLE 4 3-Hydroxy-3-( 3-ethylguanidinyl )methyl-3 ,4-dihydro 2H- 1 ,5-benzodioxepin hydiodide A mixture of S-methyl-N-ethylisothiourea hydriodide (2.46 g., 10 millimoles), 3-hydroxy-3-aminomethyl- 3,4-dihydro-2H-l,S-benzodioxepin 1.95 g. (10 millimoles) from Example 1, Step E, and 20 ml of ethanol is refluxed for four hours. The solution then is evaporated to a small volume and diluted with ether to afford 3-hydroxy-3-( 3-ethylguanidinyIl )methy1-3 ,4-dihydro- 2H-l ,S-benzodioxepin hydriodide.

EXAMPLE 5 3-Hydroxy-3-[ (2-phenylcyclohexyl )aminomethyl ]3 ,4- dihydro-ZH-l ,S-benzodioxepin hydrochloride By replacing the acetone employed in Example 1, Step F (or alternate Step F) by an equivalent quantity of 2-phenylcyclohexanone and then following essentially the same procedures described therein, there is obtained 3-hydroxy-3-[(2- phenylcyclohexyl )aminomethyl ]-3 ,4-dihydro-2H-l ,5- benzodioxepin hydrochloride, m.p. 213.5215 C.

EXAMPLE 6 3-Hydroxy-3-{[2-( 3-cyclohexyl.)propyl ]aminomethyl)- 3,4-dihydro-2H-l ,5-benzodioxepin hydrochloride By replacing the acetone employed in Example 1, Step F (or alternate Step F) by an equivalent quantity of cyclohexylacetone and then following essentially the same procedure described therein, there is obtained 3- hydroxy-3-{ [2-( 3-cyclohexyl )propyl]aminomethyl} 3.4-dihydro-2H- l ,S-benzodioxepin hydrochloride.

EXAMPLE 7 3-Hydroxy-3-dimethylaminomethyl-3.4-dihydro-2l-I- 1,5-benzodioxepin hydrochloride 3-I-Iydroxy-3-aminomethyl-3,4-dihydro-2H-l ,5- benzodioxepin (3.2 g., 0.0164 mole) from Example 1,

Step E, is added to formic acid (4.3 g., 0.082 mole). l0

EXAMPLE 8 3-Hydroxy-3-methylaminomethyl-3,4-dihydro-2I-I-1,5- benzodioxepin hydrochloride Step A: Preparation of 3-hydroxy-3-formamidomethyl- 3,4-dihydro-2H-l ,5-benzodioxepin A mixture of 1.49 g. of 97% formic acid and 3.21 g. of acetic anhydride isheated in a water bath for 2 hours (internal temperature did not exceed 55 C.) then cooled and added dropwise to a slurry of 5.86 g. of 3- hydroxy-3-aminomethyl-3,4-dihydro-2H-l ,5- benzodioxepin from Example 1, Step E, in 60 ml. anhydrous ether. A gummy white solid forms which slowly dissolves with stirring at ambient temperature overwater, twice with 10%. sodium carbonate and twice with water. The ether then is evaporated affording 2.5 g. of semi-solid material.

An oil, insoluble in either water or ether. is collected with the water and then removed by shaking'the mixture with chloroform. Upon stripping the chloroform layer there is obtained 3.6 g. of 3-hydroxy-3- formamidomethyl-3 ,4-dihydro-2H-I ,5-benzodioxepin in the form of a semi-solid, Step B: Preparation of methylaminomethyl-3 ,4-dihydro-2H-l ,5- benzodioxepin hydrochloride 3-Hydroxy-3-formamidomethyl-3,4-dihydro-2I-I-l ,5- benzodioxepin (5.8 g.) in 200 ml. anhydrous ether is added to lithium aluminum hydride (2.0 g.) in ml. of anhydrous ether dropwise in 1 hour. The mixture then is refluxed for 2 hours and the lithium then decomposed with water (5.0 ml.) followed by l0% sodium hydroxide (3.6 ml.) followed by 6.0 ml. of water. The white solid formed is filtered and the filtrate dried over magnesium sulfate then over calcium sulfate. It is stripped affording 3.8 g. of oil. The oil is acidified with UN hydrochloric acid in ethanol to give 3.7 g. of 3- hydroxy-3-methylaminomethyl-3,4-dihydro-2I-I-I .5- benzodioxepin' hydrochloride, m.p. l 89-205 C. Following several recrystallizations from ethanol, the product melts at 2172l9, C.

Other benzodioxepins prepared by the methods described in Example 1 are identified in Table I. In particular the ketone, acetone, employed in Step F of Example l is replaced by the carbonyl compound identified in the following table, which, following substantially the same procedure there described, gives the benzodioxepins I having the R substituent specified in Table 3-hydroxy-3- night. The clear liquid obtained is washed twice with 35 I.

TABLE I o OH O 7 Example 1, Step F v 3 CH NH HCl Carbonyl Reactunt CHZNHR Method 0 H H v H H- D n 'Ex. Carbonyl Empirical m.p. Analysis No. Reactant R Formula C. C H Cl N P i 9 C2H5C=O -CH(CH3)(C2H,,) C H NO .HC1 183-184 Calc. 58.43 7.71 12.32 4.87 Found 58.66 7.66 12.55 483 CH;,

10 HO -()CH2C=O -CH(CH- C,QH23NO4.H 127-129 Calc. 3.28 7.25

cH2 9-01% am.

Found 3.28 7.38

. 3 l 11 @I@CH2C=O CH(CHJ)CHZ m1) C ,H N O .HCl 190 191 Cale. 64.86 6.48 9.12 7.20 (dec.) Found 64.65 6.46 9.25 7.13

12 Cl ()CH-,C=O CH(CH-,)-CH2 C, H ClNO;,.HCll63- l65 Calc. 59.38 6.03 l8.45 3.64 i Found 59.56 6.15 |8.30 3.83

Q 8* l3 (CHz)-2C=O CH(CH3)(CH2)2 C H- NO HQ l-l83 Calc. 66.02 7.20 9.74 3.85 X Found 66.12 7.12 9.65 3.91

14 CH3CHO C H,, C,.,H,,NO .HCl l8l.5 Calc. 55.49 6.99 13.65 5.39 183 Found 5572 6.73 13.49 5.49

TABLE 1-C0ntinued H H I H H 01-1 0 on v Q0 Example 1. Step F Q: 3

CH H HCI Carbonyl Reactant CH NHR 2N r Method 0 2 H H H H H Ex. Carbonyl Empirical m.p. Analysis No. Reactant R Formula C. C H Cl N P {iv-CHO CH.-{' C|1H16NO .HCl 2l4-2l6 Cale. 63.45 6.26 11.02 4.35 Found 63.62 6.39 10.89 4.37

16 cH. cHo -(CH. c,..1-1..No..1-1c1 229-231 Calc. 64.38 6.60 10.56 4.17 d Found 64.39 6.27 10.74 4.23

17 CH C=O -CH(CH )CH C H NO HCI 170-174 Calc. 65.23 6.91 10.13 4.00

' Found 65.59 6.89 10.20 4.14 0-? -CH('CH )CH 18 CH 0 C H NO HCI 188-1895 Calc. 60.00 6.14 9.00 3.56 Found 61.02 6.14 8.91 3.38

2 CH c=o FCH C H NO HC1 220- Calc. 60.06 6.87 8.06 3.18 221.5 Found 60.24 6.9l 7.96 3.09

CH CII=O zoCH CH3 iJF'OCHg ocn.

6 l9-a =0 C H NO 1 12-1 14 Calc. 66.46 6.16 4.08 Q3 Found 66.56 6.14 3.65.

Table [I also describes additional products made by the procedure of Example 1. The products identified here areprepared by replacing the catechol employed in Step A of Example 1 by an equimolecular quantity of the catechol E having the R and Rsubstituents given in the table which then is carried through the procedures described in Steps A-E of Example 1 to provide the 3-hydroxy-3-amino-methyl compound D. Compound D thus obtained upon reaction with acetone according to the procedure described in Step F of Example 1 provides the 3,3-disubstitutedbenzodioxepin 1 having the substituents R and R in Table 11.

EXAMPLE 23 3-Hydroxy-3-( l-isopropylaminoethyl )-3 ,4-dihydro- 2H-l ,S-benzodioxepin hydrochloride given Step A: Preparation of 3-hydroxy-3-( l-nitroethyl)-3,4-

dihydro-ZH-l ,S-benzodioxepin TABLE 11 Example 1. Steps A-E OH R OH R Methods H 11 0 OH 2E11 cu m HCI R H H Example 1, Step F H H 0 OH RLUO cH NHCH(CH3)2 R H H Method Example Empirical m.p. Analysis No. R R Formula C. C Cl N 20 H CH3 CHHMNOSHCI 175 177 Calc. 58.42 7.71 12.32 4.87 Found 58.66 7.70 12.53 5.00 21 H Cl C, H,,.CINO..HCI 171- Calc. 50.66 6.21 23.01 4.54 172.5 Found 5049 6.17 23.15 4.60 22 OCH3 H C H ,|-10..C.1-1.0 155-157 C211C. 56.39 6.57 3.65 Found 56.38 6.51 3.97

n u n a n n The preparatlon of the ben2od1oxep1n bearmg an R To a so1ut1on of 3-oxo-3,4-d1hydro-2H-1,5-

substituent by the reaction of the 3-keto intermediate A with a nitroalkane. thus following the route A benzodioxepin (9.84 g., milllimoles) prepared as described in Example 1, Steps A-C in anhydrous ethanol (30 ml.) is added nitro-ethane (10 ml.) and the mixture cooled to 5 C. A solution of sodium (1.5 g., 65 millimoles) in anhydrous ethanol (30 ml.) then is added dropwise with stirring at about C. Stirring is continued at this temperature for 1 hour and for another hour at ambient temperature. Dry ether (60 ml.) is added and the mixture then stirred overnight. More dry ether (60 ml.) is added and the solid is collected after stirring the mixture for 2 hours to give 5.73 g. of product after drying in a desiccator.

Evaporation of the mother liquors to a syrup and dilution with dry ether (ca. 50 ml.) yielded a further 5.32 g. of product.

Treatment of a suspension of the combined yield of product in dry ether with a slight excess of acetic acid liberated 3-hydroxy-3-( l-nitroethyl)-3,4-dihydro-2H- 1,5 benzodioxepin which is isolated from the ethereal solution after washing the latter with water and then drying it thoroughly first magnesium sulfate and then over calcium sulfate.

Step B: Preparation of 3-( 1-aminoethyl)-3-hydroxy- 3,4-dihydro-2H-1,S-benzodioxepin hydrochloride The crude nitro compound (5.34 g., 22.3 millimoles) dissolved in a mixture of ethanol (30 ml.) and acetic acid (2 ml.) is hydrogenated at 45 C. and atmospheric pressure in the presence of Raney nickel (ca. 2.5 g.). On working up the product as its hydrogen chloride salt as described in Step E of Example 1, there is obtained 3-(1-aminoethyl)-3-hydroxy-3,4-dihydro-2H-1,5- benzodioxepin hydrochloride, m.p. l78-183 C. aftercrystallization from a mixture of isopropanol and ether.

Analysis calculated for C H NO .HC1. C, 53.77; H, 6.56; C1, 14.43; N, 5.70. Found: C, 54.06; H, 6.58; Cl, 14.68; N, 5.79.

Step C: Preparation of 3-hydroxy-3-( lisopropy1aminoethyl)-3 ,4-dihydro-2H-l ,5- benzodioxepin hydrochloride By replacing the 3-hydroxy-3-aminomethyl-3,4- dihydro-ZH-l.5-benzodioxepin hydrochloride employed in Step F of Example 1 by an equivalent quantity of 3-hydroxy-3-(l-aminoethyl)-3,4-dihydro-2H- 1,5-benzodioxepin hydrochloride and employing the same reaction conditions called for in Example 1, Step F, there is obtained 3-hydroxy-3-( 1- isopropylaminoethyl)-3,4-dihydro-2H-l ,5- benzodioxepin hydrochloride, m.p. 206-2l 1 C.

EXAMPLE 24 3-Hydroxy-3-[1-(isopropylamino)propyl]-3,4-dihydro- 2H-1,5-benzodioxepin Hydrochloride Step A: Preparation of 3-hydroxy-3-(1aminopropyl)- 3 ,4-dihydro-2H- l ,5-benzodioxepin hydrochloride By following the procedures described in Steps A and B of Example 23, but replacing the nitro-ethane by an equivalent quantity of l-nitropropane, there is obtained 3-hydroxy-3-( 1-aminopropyl)-3,4-dihydro-2H- 1,5-benzodioxepin hydrochloride, m.p. 197-l98 C. after crystallization from isopropanol.

Analysis calculated for C H NO QHCI. C, 55.49; H, 6.99; Cl, 13.65; N,5.39. Found: C, 55.28; H, 7.04; C1, 1399; N,5.57.

Step B: Preparation of 3-hydroxy-3-[1- (isopropylamino )propyl]-3 ,4-dihydro-2H- l ,5- benzodioxepin hydrochloride This product is prepared by the procedure described in Example 1, Step F, except the 3-hydroxy-3- aminomethyl-3,4-dihydro-2H-1,5-benzodioxepin employed therein is replaced by an equivalent quantity of 3-hydroxy-3-( 1-amin0propyl)-3,4-dihydro-2H- l ,5- benzodioxepin.

By following the procedure called for in Example 23, Step C, but employing the carbonyl reactant identified in Table 111, thereare obtained additional products I having an R substituent. Illustrative examples are provided in the following Table.

TABLE I11 H H O OH H H OH I C b l R Example 1. Step F cH-NH -HC| ar ony eactant 6 o 2 Mm 9; W

H H O R Example Intermediate No. from Example R Carbonyl Reactant R 25 23 CH C H C=O CH(CH:I)(C2H5) 1" 26 23 CH mom-cw CH(CH )CH -m CH;, 27 24 CH CH,-, I CH C=O CH(CH )CH m 3-spiro-2-oxirane which when reacted with an amine gives the desired product 1. that is the route D E 1 illustrated in Flow Diagram 1. It will be appreciated that'anyone of the intermediate compounds D described in this disclosure as well as others falling within the scope of its definition can be employed as starting substance and any amine of structure HNR R can be substituted for the particular amine employed to provide the desired product 1.

EXAMPLE 57 3-Hydroxy-3-t.-butylaminomethyl-3,4-dihydro-2H-l ,5- benzodioxepin hydrochloride Step A: Preparation of 3,4-dihydro-2H-l ,5- benzodioxepin-3-spiro-2-oxirane A solution of sodium nitrite (6.9 g.; 0.1 mole) in water (50 ml.) is added slowly over a period of /2 hour with stirring to a solution of 3-hydroxy-3aminomethyl- 3 .4-dihydro-2H- 1 ,S-benzodioxepin (23.17 g.; 0.1 mole), in water (200 ml.) containing acetic acid (0.1 ml.) while maintaining the reaction mixture at a temperature between about 4 to 0 C. When the addition is completed the reaction mixture then is allowed to warm to ambient temperature. The solid that forms is collected and washed with a little water to yield 14.84 g. of crude product, m.p. 132-144 C. Following recrystallization from methanol (approximately 30 parts V/W) there is obtained 11.65 g. (65.3%) of 3,4-dihydro-21-l-1,5- benzodioxepin-3-spiro-2'-oxirane, m.p. 147-149 C.

Analysis calculated for C H O 67.40; H, 5.66; O, 26.94. Found: C, 67.46; H, 5.46;O, 27.37.

Recrystallization of the crude product of Step A from chloroform also provides purified product that does not depress the melting point when taken in admixture with the purified product of Step A.

The mother liquor remaining after the removal of the crude product in Step A is extracted with ether yielding an oil 1.3 g.) which crystallizes from carbon tetrachloride to afford 300 mgs. of 3-hydroxy-3-hydroxymethyl- 3.4-dihydro-2H-l,S-benzodioxepin, m.p. 120123 C. Recrystallization of the diol from water (6 ml.) provides 254 mgs. of product, m.p. '124.5'125.5 C.

Analysis calculated for C H O C, 61.21; H, 6.17. Found: C, 61.16; H, 6.28. Y

The diol obtained described above also exhibits [3adrenergic stimulating properties and therefore is useful as a bronchial dilating agent.

Step B: Preparation of 3-hydroxy-3-L- butylaminomethyl-3,4-dihydro-2H-1 ,5benzodioxepin hydrochloride The 3,4-dihydro-2H-l,5-benzodioxepin-3-spiro-2'- oxirane (1.78 g.), obtained as described in Step A, is stirred at ambient temperature with t.-butylamine (3.2

ml.) in methanol ml.) for 42 hours. The solution then is evaporated to 2.6 g. of oil which is separated and dissolved in ether and then acidified with 1 IN HCl' j hydrochloride 26 Analysis calculated forc ll uo llcl. c. 58.43; H, 7.71; (:1. 12.32; N, 4.87.F0,und: c, 58.16; H, 7.62; cl. 12.54; N. 5.04.

EXAMPLE 58 3-Hydroxy -3-(2-dimethylaminoethyl)aminomethyl- 3,4-dihydro-2H- l ,5-benzodioxe'pin dihydrochloride "3,4-Dihydro-2H-l ,5-benzodioxepin-3-spiro-2'- oxirane (3.56 g., 20 millimoles) from Example 57. Step A. is stirred with 5.3 g. (60 millimoles) of unsymmetrical dimethylethylenediamine in 50 ml. ofmethanol for 48 hours at 30-40 C. The solution is evaporated to remove methanol and excess dimethylethylenediamine. The residual oil is dissolved in diethyl ether and acidified with ethanolic-hydrogen chloride to give crude EXAMPLE 59 3 ,4-Dihydro-2H-1,5-benzodioxepin-3-spiro-2 '-oxirane 3-Oxo-3,4-dihydro-2H-1,5-benzodioxepin (1.64 g.;

1O millimoles) from Example 1, Step C, is added slowly with stirring during l5minutes at ambient temperature to a'solution of dimethyloxosulfonium methylide pre pared under nitrogen from 15 millimoles of sodium hydride, 15 millimoles of trimethyloxosulfonium iodide, and 30 mls. of dimethyl sulfoxide. The mixture is stirred for 24 hours at ambient temperature and then 2 hours at 4550 C. The mixture is cooled and poured onto 50 g. of ice and repeatedly extracted with diethyl ether. The ethereal extract is washed with water, dried over anhydrous magnesium sulfate and evaporated. The crude productis crystallized from methanol to afford the 3,4-dihydro-2H-l ,5-benzodioxepin-3-spiro-2'- oxirane identical with the product prepared from 3- hydroxy-3-aminomethyl-3,4-dihydro-2H-l ,5- benzodioxepin as described in Example 57, Step A.

The other 3-oxo-3,4-dihydro-2H-1,S-benzodioxepins described specifically in this disclosure or falling within the scope of the definition of the 3-keto compound A can be substituted for the particular 3-keto starting substance in Example 59 to provide the desired 3-spiro- 2-oxirane of structure E.

Additional compounds prepared by theprocess described in Example 57 are identified in Table V. The products of Table V are prepared by replacing the t.- butylamine employed in Step B of Example 57 by an equimolecular quantity of the amine having the structure HNR R identified in Table V and then following substantially the same procedure described in Step B.

29 Additional 3.3-disubstituted-benzodioxepins made by the reaction of 3,4-dihydro-2H-l.5-benzodioxepin- 3-spiro-2-oxirane and an amine of the structure HNR R" by the'process described in Example 57. Step ether solution dried over magnesium sulfate and evaporated. The product obtained following crystallization from a mixture of chloroform and petroleum ether is 7-nitro-3,4-dihydro-l ,5 benzodioxepin-3-spiro-2- B. are described in Table VI. 5 oxirane.

TABLE VI O OH o Example 57 HNRR Step B 5 5 0 Method 0 CH NR R Example NO R5 R6 73 H Cl 75 H -OCH 76 z)-g' 2 2 I H 77 H2)2T(CH2)2 CH3 78 H CH2CH=CH2 79 H CH -(i=CH CH 80 H CH(CH W" 8] H CHCH2 Goa 82 H CHCH2- UK:

N l H f 83 H CHCH 84 H -CH2(CH2),,NH2

The following examples described the preparation of certain 3,3-disubstituted-benz0dioxepins having at least one substituent attached to its benzenoid moiety.

EXAMPLE 85 Step B: Preparation of 3-hydroxy-3- isopropylaminomethyl-7nitror3,4-dihydro-2H-1,5- benzodioxepin Hydrochloride By replacing the 3-spiro-2-oxirane and the t.- butylamine employed in Step B of Example 57 by equivalent quantities of 7-nitro-3,4-dihydr0-2H-l,5- benzodioxepin-3-spiro-2'-oxirane and isopropylamine respectively and then following substantially the same procedure there described, there is obtained 3- hydroxy-3-isopropyl-aminomethyl-7-nitro-3,4-dihydro- 2H-l ,S-benzodioxepin hydrochloride.

EXAMPLE 86 3-Hydroxy-3-isopropylaminomethyl-7-amino-3,4- dihydro'2H- l .S-benzodioxepin Hydrochloride Step A: Preparation of 3Acetoxy3-N acetylisopropylaminomethyl )-7nitro-3.4-dihydro-2H- 1,5-benzodioxepin Treatment of 3-hydroxy-3-isopropylaminom ethyl-7- nitro-3,4-dihydro-2H-l,S-benzodioxepin, obtained as describedin Example 85, with excess acetic anhydride and heating overnight on a water bath affords the 3- acetoxy-3-(N-acetylisopropylaminomethyl)-7-nitro- 3,4dihydro-2H-l ,5-benzodioxepin. Step B: Preparation of acetylisopropylaminomethyl)-7-amino-3,4-dihydro- 2H-l,5-benzodioxepin The 3-acetoxy-3-(N-acetylisopropylaminomethyl)-7- nitro-3,4-dihydro-2H-l,S-benzodioxepin when dissolved in ethyl acetate is reduced at low pressure over platinum with hydrogen to give 3-acetoxy-3-(N- acetylisopropylaminomethyl)-7-amino-3,4-dihydro- 2H-l ,5-benzodioxepin. Step C: 3-Hydroxy-3-(isopropylaminomethyl)-7- amino-3,4-dihydro-2H-l,5rbenzodioxepin hydrochloride 3-Acetoxy-3-(N-acetylisopropylaminomethyl)-7- amino-3,4-dihydro-2H-l,S-benzodioxepin (33.6 g., 0.1 mole) is refluxed for 10 hours with 400 ml. of methanol containing 20 g. (0.5 mole) of sodium hydroxide. The solvent is removed at low temperature in vacuo and the residue treated with 200 ml. of water. The mixture is extracted with diethyl ether and the combined ethanol phases washed with water and dried over anhydrous magnesium sulfate. The solvent is evaporated and the product, 3-hydroxy-3-(isopropylaminomethyl)-7- amino-3,4-dihydr-2H-l,5-benzodioxepin hydrochloride isolated as the hydrochloride salt.

EXAMPLE 87 3-Hydroxy-3-isopropylaminomethyl-7- methanesulfonamido-3 ,4-dihydro-2H- l ,5-

benzodioxepin Hydrochloride Step A: Preparation of 3-Acetoxy-3-(N- acetylisopropylaminomethyl)-7-methanesulfonamido- 3,4-dihydro-2H- l ,S-benzodioxepin Methanesulfonyl chloride (0.1 mole is added dropwise to a stirred solution of 0. 1 mole of 3-acetoxy-3-(N- acetoxyisopropylaminomethyl)-7-amino-3,4-dihydro- 2H-l,5-benzodioxepin, from Example 86, Step B, in l20 ml. of pyridine held at l015C. The mixture is stirred for several hours at ambient temperature, then heated to 90C. for 0.5 hours, cooled, and added to an ice-water mixture. The mixture is extracted with ether, washed, dried over magnesium sulfate, and the solvent removed to give 3-acetoxy-3-(N- acetylisopropylaminomethyl)-7-methanesulfonamido- 3,4-dihydro-2H-l ,5 benzodioxepin.' Step B: Preparation of 3-Hydroxy-3- isopropylaminomethyl-7-methanesulfonainido-3,4 dihydro-2H-1,5-benzodioxepin 3-Acetoxy-3(N-acetylisopropylaminomethyl)-7- methanesulfonamido-3,4-dihydro-2H-l ,5- I benzodioxepin (4.2 g.,-lO millimole) in 20 mlfmethanol is treated with'2 g. (50 millimoles) of sodium: hydroxide in 20 ml. of methanoll The mixture is refluxed for 3 hours, cooled, and diluted with 400 mls. of water, neutralized with acid and extracted with ether. The combinedethereal solutions are washed with water, dried over anhydrous sodium sulfate, and evaporated to give 3-hydroxy-3-isopropylaminomethyl 7- methanesulfonamido-3 ,4-dihydro-2H-l ,5- benzodioxepin.

3-Acetoxy-3-(N EXAMPLEI88,

3 -Hydroxy-3-isopropylamino:7-carbeth0xyamino-3,4-

vdihydro-Z l ll .S-benzodioxepin Step Az Preparation of 3-Acet oxy-3-(N- acetylisopropylaminomethyl)-7-carbethoxyamino-3,4- dihydro-ZH-l ,5-benzodioxepin 3-Acetoxy-3-N-acetylisopropylaminomethyl-7- amino-3,4-dihydro-2H-1,5-benzodioxepin (0.1 mole) from Example 86, Step B, in chloroform is treated with 0.1 1 mole of ethyl chloroformate and pyridine in chlo- "roform. The mixture after stirring and heating in a water bath for several hours is diluted with water, extracted with ether, the combined ethereal extracts washed, dried and evaporated to give 3-acetoxy-3-(N- acetylisopropylaminomethyl )-7-carbethoxy amino-3 ,4- dihydro-2H-1,S-benzodioxepin.

Step I B: I Preparation of 3-Hydroxy-3- isopropylaminomethyl-7-carbethoxyamino-3,4- dihydro-ZH-l ,S-benzodioxepin 3'-Acetoxy-3-( N- acetylisopropylaminomethy)-7-carbethoxyamino-3,4- dihydro-2H-l,5-benzodioxepin (4.1 g., 10 millimoles) is warmed 5 hours at 40C. with 6 ml. of concentrated hydrochloric acid and 34 ml. of ethanol. The solution is cooled, taken to the basic side with sodium hydroxide, diluted with water, and extracted with diethyl ether to give 3-hydroxy-3-isopropylaminomethyl-7- carbethoxyamino-3,4-dihydro-2H-1,S-benzodioxepin.

EXAMPLE 89 3 ,7-Dihydroxy-3-isopropylaminomethyl-3,4-dihydro- 2H-l ,5-benzodioxepin 3-Acetoxy-3-( N-acetylisopropylaminomethyl-7- amino-3,4-dihydro-2H-l ,S-benzodioxepin from Example 86, Step B, dissolved in dilute sulfuric acid is treated with sodium nitrite in water and the mixture heated on a water bath for 0.5 hours. The mixture is cooled, neutralized with base, extracted with ether, the ethereal extract washed, dried, and evaporated to give 3,7-dihydroxy-3-isopropylaminomethyl-3,4-dihydro- 2H-l ,S-benzodioxepin.

EXAMPLE 90 3-Hydroxy-3-isopropylaminomethyl-7-methoxy-3,4- dihydro-ZH-l ,S-benzodioxepin 3,7-Dihydroxy-3-isopropylaminomethyl-3,4-dihydro- 2H-l,5-benzodioxepin (2.53 g., 10 millimoles) from Example 89 dissolved in ml. of diethyl ether is left 10 hours at ambient temperaturewith 0.46 g. (ll millimoles) of diazomethane in 25 ml. of. diethyl ether. Excess diazometh'ane is destroyed by addition of a few drops of acetic acid. The solution then is washed with water, dried over anhydroussodiurn sulfate, and evaporated to dryness to give 3-hydroxy-3- isopropylaminom'ethyl- 7-methoxy=3,4-dihydro-2H-1 ,5- benzodioxepi n.

EXAMPLE 91 3-Hydroxy-3isopropylaminomethyl-7-nitro-3,4 dihydro-ZHJ .S-benzodioxepin Step A: Preparation of 3-isopropyl-3.4-dihydro-2H- l,5-benzodioxepin-3-spiro-5 -oxazolidin-2-one A mixture of 3-hydroxy-3-isopropylaminomethyl 3.4-dihydro-2H-l,S-benzodioxepin (11.85 g.; 50 millimoles), prepared as described in Example 1, and dibutyl carbonate (13.1 g.) with a small piece of metallic sodium is heated in an oil bath. The temperature then is slowly raised to 170 C. with removal of butanol. Finally the mixture is heated between l7()-200 C. with removal of excess dubutyl carbonate. The cooled reaction product is dissolved in benzene, washed with water. dried over sodium sulfate. and the solvent evaporated to give 3-isopropyl-3,4-dihydro-2H-1,5 benzodioxepin-3-spiro-5-oxazolidin-2'-one, m.p. l2l-l 22 C. Step B: Preparation of 3'-isopropyl-7-nitro-3,4- dihydro-ZH-l ,5-benzodioxepin3-spiro-5-oxazolidin- 2-one By replacing the 3,4dihydro-2H-l ,S-benzodioxepin- 3-spiro-2'-oxirane employed in Example 85, Step A, by an equivalent amount of 3'-isopropyl-3,4-dihydro-2H- l,5-benzodioxepin-3-spiro-5-oxazolidin-2-one and following substantially the same procedure there described, there is obtained 3'-isopropyl-7-nitro-3,4- dihydro-ZH-l ,5-benzodioxepin-3-spiro-5 '-oxazolidin- 2-one, m.p. l45.5147 C. Step C: Preparation of 3-hydroxy-3- isopropylaminomethyl-7-nitro-3,4-dihydro-2H- l ,5- benzodioxepin A mixture of 0.15 mole of the oxazolidinone from Step B above and 15 g. (0.38 mole) of sodium hydroxide in 100 ml. of water and 200 ml. of 95% ethanol is refluxed, the solution evaporated to a small volume and the product extracted with diethyl ether. Evaporation of the solvent gives 3-hydroxy-3- isopropylaminomethyl-7-nitro-3,4-dihydro-2H-l ,5- benzodioxepin.

EXAMPLE 92 3-Hydroxy-3-isopropylaminomethyl-7- methanesulfonamido-3,4-dihydro-2H-1,5- benzodioxepin Step A: Preparation of 3'-isopropyl-7-amino-3,4- dihydro-2H-1,5-benzodioxepin-3-spiro-5 '-oxazolidin- 2-one By replacing the 3-acetoxy-3-N- acetylisopropylaminomethyl-7-nitro-3,4-dihydro-2H- 1,5-benzodioxepin used in Example 86, Step B, by an equivalent quantity of 3'-isopropyl-7-nitro-3,4- dihydro-ZH- l ,5-ben2odioxepin-3-spiro-5 -oxazolidin- 2-,one obtained as described in Example 91, Step B, and then following substantially the procedure described in Example 86, Step B, there is obtained 3'- isopropyl-7-amino-3 ,4-dihydro-2H-l ,S-benzodioxepin- 3-spiro-5-oxazolidin-2-one. Step B: Preparation of 3 '-isopropyl-7- methanesulfonamido-3,4-dihydro-2H-1,5- benzodioxepin-3-spiro-5'-oxazolidin-2'-one By reacting the oxazolidinone obtained in Step A with methanesulfonyl chloride and employing the other reaction conditions and procedure described in Example 87. Step A, there is obtained v3-isopropyl-7- methanesulfonamido-3,4-dihydro-2H-l .5- benZodioxepin-3-spiro-5'-oxazolidin 2'-one. Step C: Preparation of 3-hydroxy-3- isopropylaminomethyl-7-methanesulfonamido-3,4- dihydro-2H-1.S-benzodioxepizn This product is prepared by substituting the oxazolidinone compound of Step-B above for that employed in Example 91, Step C, and following essentially the same reaction there described.

EXAMPLE 93 3-Hydroxy-3-isopropylaminomethyl-7- carbethoxyamino-3,4-dihydro- 2H- l ,S-benzodioxepin Step A: Preparation of 3 -isopropyl-7- ethoxycarbonylamino-3 ,4-di'hydro-2H- l ,5- benzodioxepin-3-spiro5 '-oxazolidin-2-one By replacing the 3-acetoxy-3-N- acetylisopropylamino-7-aminc-3,4-dihydro-2H-l ,5- benzodioxepin reactant in Example 88, Step A, by the 3 -isopropyl-7-amino-3,4-dihydro-2l-l-l ,5- benzodioxepin-3-spiro-5'-oxazolidin-2'-one, prepared as described in Example 92, Step A, and then following substantially the same procedure described in Example 88, Step A, there is obtained 3'-isopropyl-7 carbethoxyamino-3 ,4-dihydro-2H- l ,5 -benzodioxepin- 3-spiro-5'-oxazolidin-2'-one. Step B: Preparation of I 3-hydroxy-3- isopropylaminomethyl-7-carbethoxyamino-3,4- dihydro-ZH-l ,S-benzodioxepin The oxazolidinone from Step A above is refluxed in ethanol containing anhydrous hydrogen chloride. The solution is neutralized, evaporated to a small volume, diluted with water and extracted with ether. The dried ethereal solution is evaporated. to give the desired product. I

EXAMPLE 94 3,7-Dihdyroxy-3-isopropylaminomethyl-3,4-dihydro- ZH-l ,S-benzodioxepin Step A: Preparation of 3 -isopropyl-7-hydroxy-3,4- dihydro-2H- l ,5-benzodioxepin-3-spiro-5 '-oxazolidin- 2'-one This product is prepared by following the procedure and employing the reactants and reaction conditions described in Example 89 except the 3-acetoxy-3-N- acetylisopropylaminomethyl7-amino-3,4-dihydro-2H- 1,5-benzodioxepin there employed is replaced by the oxazolidinone obtained as described in Example 92, Step A.

Step B: Preparation of 3,7-dihydroxy-3- isopropylaminomethyl'3,4-dihydro-2H-1,5- benzodioxepin This product is prepared by substituting the oxazolidinone compound of Step A above for that employed in Example 91, Step C, and following essentially the same reaction there described.

EXAMPLE 95 3-Hydroxy-3-isopropylaminomethyl-7-methoxy-3 ,4- dihydro-ZH-l ,S-benzodioxepin Step A1 Preparation of 3-isopropyl-7-methoxy-3,4- dihydro-ZH-1,5-benzodioxepin-3-spiro-5 -oxazolidin- 2-one of 3-hydroxy-3- EXAMPLE 96 3,6-Dihydroxy-3-isopropylaminomethyl-3,4-dihydro- 2H-l ,S-benzodioxepin Hydrochloride Step A: Preparation of 2-methoxy-2-methyl-4-hydroxy- 1,3-benzodioxole A mixture of pyrogallol (25.2 g., 0.2 mole) and trimethyl orthoacetate (26.4 g., 0.22 mole) is treated with one drop of concentrated sulfuric acid and the reaction mixture then stirred under nitrogen in an oil bath at l03105 C. Methanol formed in the reaction is distilled up a short column and collected. After 1 hour, more trimethyl orthoacetate (2 g., 0.016 mole) and another drop of sulfuric acid are added and the temperature of the oil bath raised to 1081 C. for a further hour. Methanol (9.6 ml.) is collected. On cooling, the dark brown oil crystallizes and is dissolved in ether (120 ml.), the ethereal solution is washed with 2% sodium carbonate solution (50 ml.) and then with saturated sodium chloride solution. Evaporation of the dried ethereal solution yields 31.2 g. of a pale yellow solid. The crude product is dissolved in boiling carbon tetrachloride (280 ml.) and some solid (mainly pyrogallol) is removed by filtration. On cooling, the solution yields 24.24 g. (66.6%) of 2-methoxy-2-methyl-4- hydroxy-1,3-benzodioxole, m.p. lO6109 C. Upon further recrystallization of the compound from carbon tetrachloride, with treatment with charcoal and activated alumina, the product melts at 1 l4.51l5.5 C.

Analysis calculated for C H O C, 59.33; H, 5.53. Found: C, 59.70; H, 5.85. Step B: Preparation of 2-Methoxy-2-methyl-4- benzyloxy-l ,3-benzodioxole To a suspension of sodium hydride (2.4 g., 0.1 mole) in freshly distilled hexamethyl-phosphoramide (24 ml.) is added dropwise with stirring under dry nitrogen a solution of 2-methoxy-2-methyl-4-hydroxy-1 ,3- benzodioxole (18.2 g., 0.1 mole) in hexamethylphosphoramide (36 ml.) and stirring is continued at ambient temperature until hydrogen evolution essentially ceases. Benzyl chloride (12.65 g., 0.1 mole) is added and the mixture stirred at 75-80 C. for 5 hours. The mixture then is poured onto ice and adjusted to ca. pH 6 with acetic acid. The product is extracted with ether, and the ethereal solution washed with 2% sodium carbonate solution (50 ml.) and then with saturated sodium chloride solution. After drying over magnesium sulphate and then calcium sulfate, the ethereal solution is evaporated to give 2-methoxy-2methyl-4-benzyloxy-1,B-benzodioxole which can be crystallized from di-isopropyl ether. Step C: Preparation of 3-benzyloxy-catechol A mixture of 2-methoxy-2-methyl-4-benzyloxy-1,3- benzodioxole (13.6 g., 0.05 mole), methanol (210 ml.) and 5N hydrochloric acid (210 ml.) is stirred under reflux in an atmosphere of nitrogen for 10 hours. Most of the methanol is distilled off under vacuum and the product then extracted with ether. The ethereal solution is washed with water, dried over magnesium sulfate followed by calcium sulfate and evaporated to dryness to yield the crude 3-benzyloxy-catechol which can be recrystallized from di-isopropyl ether.

Step D: Preparation of 3-amino-4-cyano-6-benzyloxy- 3,4-dihydro-2H- l ,S-benzodioxepin By replacing catechol employed in Step A of Example 1 by an equivalent quantity of 3-benzyloxycatechol and following substantially the same procedures described in Steps A and B of Example l there are obtained sequentially 1,2-di( cyanomethoxy)-3- benzyloxybenzene and then 3-amino-4- cyano-6-benzyloxy-3,4-dihydro-2H-1,5-benzodioxepin and/or the 9-benzyloxy isomer. Step E: Preparation isopropylaminomethyl- 3,4-dihydro-2H-1,S-benzodioxepin hydrochloride The 3-amino-4-cyano-6-benzyloxy-3,4-dihydro-2H- 1,5-benzodioxepin and/or its 9-benzyloxy isomer is converted to 3-oxo-6-benzyloxy-3,4-dihydro-2H-1,5- benzodioxepin by the procedure described in Example 1, Step C, and the 3-keto compound'then reacted with potassium cyanide by either the process of Step D of Example 1 or the alternative procedure there described to provide 3-hydroxy-3-cyano-6-benzyloxy- 3,4-dihydro-2H-1,5-benzodioxepin. This product then is reduced with lithium aluminum hydride by the method outlined in the alternate of Step E, Example 1, to give 3-hydroxy-3- aminomethyl-6-benzyloxy-3,4-dihydro-2H-l ,5- benzodioxepin which when reacted with acetone and then reduced by the process of Step F, Example 1, there is obtained 3,6-dihydroxy- 3-isopropylaminomethyl-3 ,4-dihydro-2H- l ,5- benzodioxepin hydrochloride.

Additional 3,3-disubstitute d-benzodioxepins having at least one substituent attached to the benzenoid moiety that can be prepared from the appropriate catechol by any of the major routes illustrated in Flow Diagram [1 followed by any of the procedures illustrated in Flow Diagram 1 are identified in the following Table. For convenience the catechols identified in Table VI] are converted to the 3-oxo-benzodioxepin by substantially the same methods described in Example 1, Steps A through C (that is route E F 4 G A in Flow Diagram 11). The other route (that is E F G A) described in Examples 108 and 109 could have been employed to provide the 3-oxo-benzodioxepin A and the following table is to be understood as applying to this route as well. Also, for convenience the end products 1 are prepared by the procedures described in Examples 1, Steps D through F, Example 23 or Example 57, as indicated in the table (that is route A C D l;A B D l,andA C D E 1) although the other modifications illustrated in Flow Diagram 1 and in the Examples could equally be employed.

of 3,6-dihydroxy-3- TABLE VII 3 3 X X R H X H OH OH Example I See Table for I on Steps A c R Method R o CHNHR Method 0 I H H R4 R R H H R Method For FX A 1 H01 R R x R R R Ex. No. Step 97 H (CH, ):C- H H H CH(CHJ)Z l or 9x H (CH;);C CH3 H H CH(CHJ)Z 57 A-B 99 H (CH;;) 1C (CHmC- H CH(CH3)2 123 C 100 H (CHn cH- (CH3)2CH H H C(CH )a 57 AB lOl (CH CH- H (CH hCH- H H CH(CH=,)2 1 DP i I02 (CHmCH- H CH -CHCH 23 A-C 103 H 3)2CH H C(CH3)3 57 A-B 107 H Ho H H H 57 A-B EXAMPLE 108 3-Hydroxy-3-isopr0pylaminomethyl-3 ,4-dihydro-2H- l,5-benzodioxepin Hydrochloride Step A: Preparation of l,Z-bis-carbomethoxymethoxybenzene (or l,2-benzene-bis methyl glycolate) Methyl bromoacetate (57 g.) is added portionwise to a mixture of catechol (24 g.), potassium carbonate (62 g.), potassium iodide (3g) and acetone (500 ml.). The reaction gradually warmed up and a precipitate formed. The reaction mixture then was stirred overnight at ambient temperature and the precipitated substance removed by filtration. The acetone solution was distilled to remove the acetone whereupon an oily residue was obtained which was crystallized from methanol yielding 27 g. of l,2-bis-carbomethoxymethoxybenzene.

Step B: Preparation of 3-oxo-4-carbomethoxy-3,4- dihydro-ZH-l .5-benz0dioxepin.

Potassium tt-butoxide (15.8 g.) dissolved in DMSO (130 ml.) is added dropwise over a 45 minute period to l.2-bis-carbomethoxymethoxybenzene (18.3 g.) in DMSO (30 ml.) under an atmosphere of nitrogen. The mixture then is stirred 3 hours at ambient temperature and a mixture of acetic acid (16 ml.) and water (200 ml.) is added. The reaction mixture is extracted with benzene. the powdery material removed by filtration and the benzene then dried over magnesium sulfate and the benzene then evaporated leaving 3-oxo-4- carbomethoxy-3,4-dihydro-2ll-l ,S-benzodioxepin that is used in the following step without purification.

sodium bicarbonate solution, then twice with 50 ml.

portions of water. After drying the washed ether extract over magnesium sulfate and evaporation to remove the solvent there is obtained 3-oxo-3,4-dihydro- ZH-l ,S-benzodioxepin.

Step D: Preparation of 3-hydroxy-3- isopropylaminomethyl- 3,4-dihydro-2H- l ,S-benzodioxepin hydrochloride The 3-oxo-3,4-dihydro-2H- 1 ,S-benzodioxepin is converted to the desired 3-hydroxy-3-isopropylaminomethyl-3,4- dihydro-ZH-l ,5-benzodioxepin hydrochloride by the procedures described in Example 1. 

1. A 3,3-DISUBSTITUTED-BENZODIXEPIN HAVING THE STRUCTURE
 2. A 3,3-disubstituted-benzodioxepin as claimed in claim 1 wherein R,R1,X,X1,R2,R3 and R5 each represent hydrogen, R4 represents lower alkyl and R6 has the meaning assigned in claim
 3. A 3,3-disubstituted-benzodioxepin as claimed in claim 1 wherein R,R1,X,X1,R2,R3,R4, and R5 each represent hydrogen and R6 have the meaning assigned to each in claim
 1. 4. A 3,3-disubstituted-benzodioxepin as claimed in claim 1 wherein R,R1,X,X1,R3 and R5 each represent hydrogen and R2,R4 and R6 have the meaning assigned to each in claim
 1. 5. A product as claimed in claim 3 wherein R6 is 3-morpholinopropyl. 